Vol. 116, August Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1976 by The Williams & Wilkins Co.
THE ABSORPTION OF ANTIBIOTICS FROM THE BLADDER GEOFFREY CHAMBERLAIN
AND
PETER NEEDHAM*
From the Chelsea Hospital for Women, London, England
ABSTRACT
The movement across the bladder epithelium of polymyxin B, bacitracin and neomycin is investigated in the human during postoperative irrigation. No appreciable amounts of these antibiotics enter the systemic circulation by this route. The bladder is a storage organ lined with transitional epithelium. This lining used to be considered an impermeable barrier, across which absorption of water or solutes could not take place but, more recently, investigators have shown the passage of water, 1 glucose 2 and various. drugs_ such .as nitrofurantoin 3 from the bladder into the circulat10n. While some have investigated the transvesical transportation of many other physiological and pharmaceutical preparations few seem to have examined the absorption of antibiotics from this organ. Solutions now being instilled into the bladder to prevent postoperative infection contain polymyxin B, bacitracin and neomycin. All of these drugs have potentially toxic side eff~cts in the body if concentrations accumulate and the theoretical risk of transepithelial transport should be considered. All of these antibiotics are composed of large molecules with low lipid solubility and show poor absorption through the gastrointestinal tract. 4 It would appear, therefore, that passage through biological membranes is likely to be limited and it seemed reasonable to investigate patients having bladder irrigations with these substances after a gynecological operation to see if the antibiotics passed from the bladder into the systemic circulation. METHODS
We selected 17 patients who were undergoing vaginal operations for non-malignant reasons. Nine patients had a vaginal hysterectomy and repair while 8 had an anterior and posterior repair only. All operations were done by the same team of surgeons and all patients had a 14F catheter inserted at the end of the operation. A disposable irrigation systemt was used so that the bladder could be irrigated at regular intervals and then completely emptied by a capillary system. 5 The irrigation solution contained 1 ampule of soluble+ in 500 ml. sterile saline and was replaced every 6 hours. The urine produced during the first 6 hours was collected and a 10 ml. aliquot was removed after the total volume was measured. In 14 patients 10 ml. samples of venous blood were taken 10 and 30 minutes after the commencement of irrigation. The double blood sampling was performed again after 5 days of irrigation in 15 patients. All samples were deep frozen and analyzed in batches. The analyses were done by microbiological assays and the organisms used for the different antibiotics are given in table 1. For each sample standard graphs for each antibiotic of concentration against the diameter of the zone of inhibition were obtained. To determine the concentration of antibiotic in the test sample the diameter of the zone of inhibition (if present) was compared to the standard graph and the concen-
tration was read off. We did 4 estimations on each sample and took the average. (Further details of the assays are available on request.) RESULTS
Tables 2 and 3 show the levels of polymyxin B, bacitracin and neomycin found in each of the samples on days 1 and 5, 10 and 30 minutes after the start of infusion. Table 2 also shows details of the urinary levels of these antibiotics. The lower limit for the concentration on the standard curve varies from assay to assay for the same antibiotic. This variance is caused by minor differences in humidity and water content of the test plates, temperature or other factors that can affect the diffusion of the antibiotic into the culture medium and alter the size of the zone of inhibition. Because of the structure of the assay the concentration of antibiotic in the test sample could often only be expressed as less than x units per ml. since there was no quantifiable inhibition less than this concentration in the standard series. Thus, the concentration in any test sample that had a zone of inhibition less than this could only be so expressed. In most cases there was no significant amount of any of the 3 antibiotics found in the blood immediately after starting an infusion nor in the 5-day samples. In all cases a high concentration of the antibiotic was found in the fluid removed from the bladder. With short-term and relatively long-term sampling methods it seems that in only 3 patients did any significant amount of these antibiotics cross from the bladder into the circulation: polymyxin in J. J. on day 1 (table 2) and neomycin in E. B. on day 1 (table 2) and in M. H. on day 5 (table 3). DISCUSSION
Since postoperative patients receive increasing quantities of medication, it is important to show that a commonly used antibiotic mixture in an irrigating fluid is not usually absorbed from the bladder when other substances obviously are. From these results there is evidence that little absorption of polymyxin or neomycin occurs and no patients showed any bacitracin in the blood. All of these antibiotics can be nephrotoxic, the incidence and degree of toxicity increasing with increased plasma levels. The neomycin levels in E. B. on day 1 and M. H. on day 5 are less than the lower level of 13.6 units per ml. quoted by Martmdale, • while the polymyxin level in J. J. on day 1 is just in the
Accepted for publication December 23, 1975. * Current address: St. Bartholemew's Hospital, E.C. 1, London, England. t Cystomat. Leo Laboratories Ltd., Uxbridge Rd., Hayes, Middlesex, England. :j: Polybacterin Soluble G.U., Wellcome Foundation Ltd., Ravens Lane, Berkhamstead, Hertford England.
TABLE
1. The organisms and media used for the microbiological
assays of the antibiotics Assay
Test Organism
Code
Test Medium
CN385
WRL nutrient agar
Bacitracin
Bordetella bronchiseptica Micrococcus flavus
CN4125
Neomycin
Bacillus pumilus
CN4235
Difeo antibiotic medium No. 1 Difeo antibiotic medium No. 11
Polymyxin B
172
173
ABSORPTION OF ANTIBIOTICS FROM BLADDER TABLE
2. Urine and plasma levels of the antibiotics on day 1 expressed as units per milliliters Plasma
Urine
30 Minutes
10 Minutes
GD FK
HM SA EB
MH AB JJ KL
vw
MN JS KS BR
TABLE
Polymyxin
Bacitracin
Neomycin
19.6 53.0 112.5 56.7 45.3 80.0 39.4 46.8 23.6 123.0 28.5 46.5 138.0 67.5
1.17 1.84 1.64 1.36 1.36 1.44 0.8 1.12 0.7 1.2 0.3 0.5 1.4 1.0
13.0 38.6 34.7 20.0 21.3 7.2 10.5 27.0 7.2 20.0 7.2 9.5 18.0 11.3
Polymyxin
THE JOURNAL OF UROLOGY
Copyright© 1976 by The Williams & Wilkins Co.
THE ABSORPTION OF ANTIBIOTICS FROM THE BLADDER GEOFFREY CHAMBERLAIN
AND
PETER NEEDHAM*
From the Chelsea Hospital for Women, London, England
ABSTRACT
The movement across the bladder epithelium of polymyxin B, bacitracin and neomycin is investigated in the human during postoperative irrigation. No appreciable amounts of these antibiotics enter the systemic circulation by this route. The bladder is a storage organ lined with transitional epithelium. This lining used to be considered an impermeable barrier, across which absorption of water or solutes could not take place but, more recently, investigators have shown the passage of water, 1 glucose 2 and various. drugs_ such .as nitrofurantoin 3 from the bladder into the circulat10n. While some have investigated the transvesical transportation of many other physiological and pharmaceutical preparations few seem to have examined the absorption of antibiotics from this organ. Solutions now being instilled into the bladder to prevent postoperative infection contain polymyxin B, bacitracin and neomycin. All of these drugs have potentially toxic side eff~cts in the body if concentrations accumulate and the theoretical risk of transepithelial transport should be considered. All of these antibiotics are composed of large molecules with low lipid solubility and show poor absorption through the gastrointestinal tract. 4 It would appear, therefore, that passage through biological membranes is likely to be limited and it seemed reasonable to investigate patients having bladder irrigations with these substances after a gynecological operation to see if the antibiotics passed from the bladder into the systemic circulation. METHODS
We selected 17 patients who were undergoing vaginal operations for non-malignant reasons. Nine patients had a vaginal hysterectomy and repair while 8 had an anterior and posterior repair only. All operations were done by the same team of surgeons and all patients had a 14F catheter inserted at the end of the operation. A disposable irrigation systemt was used so that the bladder could be irrigated at regular intervals and then completely emptied by a capillary system. 5 The irrigation solution contained 1 ampule of soluble+ in 500 ml. sterile saline and was replaced every 6 hours. The urine produced during the first 6 hours was collected and a 10 ml. aliquot was removed after the total volume was measured. In 14 patients 10 ml. samples of venous blood were taken 10 and 30 minutes after the commencement of irrigation. The double blood sampling was performed again after 5 days of irrigation in 15 patients. All samples were deep frozen and analyzed in batches. The analyses were done by microbiological assays and the organisms used for the different antibiotics are given in table 1. For each sample standard graphs for each antibiotic of concentration against the diameter of the zone of inhibition were obtained. To determine the concentration of antibiotic in the test sample the diameter of the zone of inhibition (if present) was compared to the standard graph and the concen-
tration was read off. We did 4 estimations on each sample and took the average. (Further details of the assays are available on request.) RESULTS
Tables 2 and 3 show the levels of polymyxin B, bacitracin and neomycin found in each of the samples on days 1 and 5, 10 and 30 minutes after the start of infusion. Table 2 also shows details of the urinary levels of these antibiotics. The lower limit for the concentration on the standard curve varies from assay to assay for the same antibiotic. This variance is caused by minor differences in humidity and water content of the test plates, temperature or other factors that can affect the diffusion of the antibiotic into the culture medium and alter the size of the zone of inhibition. Because of the structure of the assay the concentration of antibiotic in the test sample could often only be expressed as less than x units per ml. since there was no quantifiable inhibition less than this concentration in the standard series. Thus, the concentration in any test sample that had a zone of inhibition less than this could only be so expressed. In most cases there was no significant amount of any of the 3 antibiotics found in the blood immediately after starting an infusion nor in the 5-day samples. In all cases a high concentration of the antibiotic was found in the fluid removed from the bladder. With short-term and relatively long-term sampling methods it seems that in only 3 patients did any significant amount of these antibiotics cross from the bladder into the circulation: polymyxin in J. J. on day 1 (table 2) and neomycin in E. B. on day 1 (table 2) and in M. H. on day 5 (table 3). DISCUSSION
Since postoperative patients receive increasing quantities of medication, it is important to show that a commonly used antibiotic mixture in an irrigating fluid is not usually absorbed from the bladder when other substances obviously are. From these results there is evidence that little absorption of polymyxin or neomycin occurs and no patients showed any bacitracin in the blood. All of these antibiotics can be nephrotoxic, the incidence and degree of toxicity increasing with increased plasma levels. The neomycin levels in E. B. on day 1 and M. H. on day 5 are less than the lower level of 13.6 units per ml. quoted by Martmdale, • while the polymyxin level in J. J. on day 1 is just in the
Accepted for publication December 23, 1975. * Current address: St. Bartholemew's Hospital, E.C. 1, London, England. t Cystomat. Leo Laboratories Ltd., Uxbridge Rd., Hayes, Middlesex, England. :j: Polybacterin Soluble G.U., Wellcome Foundation Ltd., Ravens Lane, Berkhamstead, Hertford England.
TABLE
1. The organisms and media used for the microbiological
assays of the antibiotics Assay
Test Organism
Code
Test Medium
CN385
WRL nutrient agar
Bacitracin
Bordetella bronchiseptica Micrococcus flavus
CN4125
Neomycin
Bacillus pumilus
CN4235
Difeo antibiotic medium No. 1 Difeo antibiotic medium No. 11
Polymyxin B
172
173
ABSORPTION OF ANTIBIOTICS FROM BLADDER TABLE
2. Urine and plasma levels of the antibiotics on day 1 expressed as units per milliliters Plasma
Urine
30 Minutes
10 Minutes
GD FK
HM SA EB
MH AB JJ KL
vw
MN JS KS BR
TABLE
Polymyxin
Bacitracin
Neomycin
19.6 53.0 112.5 56.7 45.3 80.0 39.4 46.8 23.6 123.0 28.5 46.5 138.0 67.5
1.17 1.84 1.64 1.36 1.36 1.44 0.8 1.12 0.7 1.2 0.3 0.5 1.4 1.0
13.0 38.6 34.7 20.0 21.3 7.2 10.5 27.0 7.2 20.0 7.2 9.5 18.0 11.3
Polymyxin
